Liver cancer is the fifth most common form of cancer. Each year, approximately 750,000 cases are diagnosed and about 700,000 people die from the disease each year, making it the third most common cause of cancer death in the world (Ferlay et al., Int. J. Cancer 127:2893-2917 (2010)). In the United States, the incidence of primary liver cancer has been rising, and while some progress has been made in detecting and treating localized disease, the five year survival rate for late stage liver cancer is still well below 10% (American-Cancer-Society. 2012. Cancer Facts & Figures 2012. Atlanta: American Cancer Society).
Established treatments for liver cancer include surgical removal of the part of the liver containing the tumor (partial hepatectomy), liver transplantation, transcatheter arterial chemoembolization (TACE), in situ tumor destruction by various methods such as radiofrequency ablation (RFA) or cryosurgery and administration of Sorafenib. Treatment options for late stage liver patients are limited. Thus, effective treatments of liver cancer remains a significant unmet medical need.
The role of Notch signaling in liver cancer is not well understood. Qi et al. report that Notch1 signaling inhibits growth of human hepatocellular carcinoma cells in vitro and in vivo by inducing cell cycle arrest and apoptosis (Qi et al., Cancer Res. 63:8323 (2003)) and Viatour et al. report that expression of Notch1 intracellular domain decreased proliferation and induced apoptosis in murine and human HCC cells (Viatour et al., J. Exp. Med. 208(10):1963 (2011)). Others report that Notch1 small interfering RNA (siRNA) reduced cell invasion and migration but not viability (Zhou et al. Dig. Dis. Sci.). Yet others report that inhibition of individual Notch pathway family members had no effect. Taken together, the Notch pathway's role in liver cancer was not well understood.